Modulating anti-HIV immunity by plasmacytoid dendritic cells

人浆细胞样树突状细胞(PDC)是一种罕见的血树突状细胞(DC)亚群，与 来源于髓系CD11c+的“常规”树突状细胞(CDC)。通过在体内产生高水平的I型干扰素 对病毒感染的反应，PDC是天然和获得性抗病毒免疫之间的关键纽带 回应。我的实验室最近的观察强调了它们在免疫中的特殊作用 HIV-1感染的调控。PDC，但不是CDC，在CD4介导后经历激活 HIV-1的内吞作用和TLR7随后与基因组RNA的激活。激活的PDDC 上调共刺激分子，产生促炎细胞因子和趋化因子并激活 不成熟的疾控中心以旁观者的方式。作为诱导这些抗病毒反应的对立面， HIV激活的pDC同时诱导幼稚T细胞分化 静息的CD4+T细胞。Treg的产生需要表达吲哚胺2，3-双加氧酶(IDO)，以及 一种将色氨酸分解为犬尿氨酸的酶，当加入特定的 1甲基色氨酸抑制剂。产生的T调节子(“可诱导的T调节子”)抑制细胞的增殖。 激活T细胞和CDC成熟，从而减弱正在进行的适应性免疫的诱导 回应。因此，pDC抑制病毒复制，促进抗病毒免疫，但同时 限制免疫激活的程度。这种新发现的pDC特性与HIV病毒尤其相关 控制过度免疫激活对预防病毒至关重要的感染 疾病的传播和发展。在本应用程序中，我们建议：(1)识别 HIV依赖、PDC诱导T细胞分化的机制(S)，特别关注 IDO；(2)确定Tregs用于抑制T细胞生长和CDC激活的调节过程； (3)确定是否可以调节PDC诱导的Tregs的抑制活性以增强 艾滋病毒特异性适应性免疫反应。这些研究将极大地提高我们对 HIV激活PDC后发生的事件，并可能导致临床适用的方法 增强体内抗HIV免疫反应。

Human plasmacytoid dendritic cells (pDC) constitute a rare subset of blood dendritic cells (DC), distinct from myeloid CD11c+, “conventional” DC (cDC). Through production of high levels of type I IFN in response to virus infection, pDC serve as a critical link between innate and adaptive antiviral immune responses. Recent observations from my laboratory have highlighted their particular role in the immune regulation of HIV-1 infection. pDCs, but not cDCs, undergo activation following CD4 mediated endocytosis of HIV-1 and subsequent activation of TLR7 with genomic RNA. Activated pDCs upregulate costimulatory molecules, produce pro-inflammatory cytokines and chemokines and activate immature cDCs in a bystander fashion. As a counterpoint to the induction of these anti-viral responses, HIV-activated pDCs simultaneously induce the differentiation of Tregulatory cells (Tregs) from naïve resting CD4+ T cells. Treg generation requires the expression of indolamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan to kynurenine, as it is reversed upon addition of the specific inhibitor 1 methyl-tryptophan. The T regs generated (“inducible T regs”) inhibit the proliferation of activated T cells and maturation of cDC, thereby attenuating the induction of ongoing adaptive immune responses. Thus pDCs inhibit viral replication and promote anti-viral immunity, but at the same time limit the extent of immune activation. This newly ascribed property of pDCs is especially relevant in HIV infection where control of excessive immune activation could be essential to prevent virus dissemination and progression of disease. In this application we propose to: (1) identify the mechanism(s) underlying HIV-dependent, pDC-induced T reg differentiation, focusing in particular on IDO; (2) determine the regulatory processes used by Tregs to inhibit T cell growth and cDC activation; (3) establish whether the inhibitory activity of pDC induced-Tregs can be modulated in order to enhance HIV-specific adaptive immune responses. These studies will greatly improve our understanding of the events that follow pDC activation by HIV and potentially result in clinically applicable approaches to enhance anti-HIV immune responses in vivo.